Project 1) Selective effects of active metabolites of 1-B-D-arabino-furanosylcytosine (ara-C) in vivo. By using a well established tumor line, L1210, and an extensively studied antitumor agent, ara-C, the research work will be directed to gain insight into the following problems of chemotherapeutic relevance: Is DNA synthesis in L1210 leukemic cells and in host cell renewal systems differently affected by the active metabolite of ara-C (i,e., ara-CTP)? Are there differences between normal and leukemic cells in the relationship between dose of ara-C and duration of cytotoxic concentrations of ara-CTP? Are the lethal effects of inhibition of DNA synthesis by ara-CTP quantitatively similar in both kinds of cells? Project 2) Biochemical manipulation of ara-C metabolism in human leukemic cells. The information obtained from Project 1 will be utilized to design experiments to compare the metabolism of ara-C in human leukemic and normal hemopoetic cells in vitro. The ability of these cells to synthesize ara-CTP in the presence and absence of tetrahydrouridine (THU) will be analyzed. It is known that human leukemic cells and other cells contain pyrimidine nucleoside deaminase (PND) which converts ara-C to inactive metabolite, ara-U; and that THU is a potent inhibitor of PND. It is hoped that combined use of THU and ara-C will selectively increase intracellular ara-CTP in leukemic cells and thus increase therapeutic efficacy of ara-C.